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UPA Perpustakaan Universitas Jember

Biology of Mood & Anxiety Disorders

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Background: Coordination of activity between the amygdala and ventromedial prefrontal cortex (vmPFC) is
important for fear-extinction learning. Aberrant recruitment of this circuitry is associated with anxiety disorders. Here,
we sought to determine if individual differences in future threat uncertainty sensitivity, a potential risk factor for
anxiety disorders, underly compromised recruitment of fear extinction circuitry.
Twenty-two healthy subjects completed a cued fear conditioning task with acquisition and extinction phases. During
the task, pupil dilation, skin conductance response, and functional magnetic resonance imaging were acquired. We
assessed the temporality of fear extinction learning by splitting the extinction phase into early and late extinction.
Threat uncertainty sensitivity was measured using self-reported intolerance of uncertainty (IU).
Results: During early extinction learning, we found low IU scores to be associated with larger skin conductance
responses and right amygdala activity to learned threat vs. safety cues, whereas high IU scores were associated
with no skin conductance discrimination and greater activity within the right amygdala to previously learned
safety cues. In late extinction learning, low IU scores were associated with successful inhibition of previously
learned threat, reflected in comparable skin conductance response and right amgydala activity to learned threat
vs. safety cues, whilst high IU scores were associated with continued fear expression to learned threat, indexed by
larger skin conductance and amygdala activity to threat vs. safety cues. In addition, high IU scores were associated with
greater vmPFC activity to threat vs. safety cues in late extinction. Similar patterns of IU and extinction learning were
found for pupil dilation. The results were specific for IU and did not generalize to self-reported trait anxiety.
Conclusions: Overall, the neural and psychophysiological patterns observed here suggest high IU individuals to
disproportionately generalize threat during times of uncertainty, which subsequently compromises fear extinction
learning. More broadly, these findings highlight the potential of intolerance of uncertainty-based mechanisms to
help understand pathological fear in anxiety disorders and inform potential treatment targets.

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